Cyanoacrylic acid ester-substituted 2- and 7-azaindoles mediate potency, efficacy, and specificity toward the monocarboxylate transporters (MCTs) 1 and 4.

Monocarboxylate transporters (MCTs) have been associated with cancer cell migration, invasion, and metastases with poor prognoses in various cancers. MCT1 and MCT4 have been identified as potential cancer markers and drug targets; several medicinal chemistry campaigns have provided drug candidates to pre-clinical and clinical stages. However, ligand development for MCTs is stalling, and several reasons can be identified, e.g., ultra-high potency-triggered on-target toxicity and compensation, isoform unselectivity, ubiquitous MCT expression, unspecificity over other targets, and MCTs-mediated multidrug resistance (MDR). The aim of the present study was the design of 2-azaindole (i.e., indazole) and 7-azaindole derivatives with moderate and balanced potency against MCT1 and MCT4, designed-out off-target effects on ATP-binding cassette (ABC) transporters, and efficacy in various in vitro cancer cell models. We identified cyanoacrylic acid ester-substituted indazoles that could optimally translate their functional MCT1 inhibition into efficacy against MCT1-expressing A-549 cancer cells. These compounds showed also efficacy against MCT4-expressing MDA-MB-231 cells, and correlation analyses on Hill slopes from functional and MDR reversal analyses pinpointed to a causal relationship between MCT1 and MCT4 inhibition and triggered cancer cell death. Glucose supplementation reversed cancer cell toxicity, while lead compounds could sensitize cancer cells toward doxorubicin and metformin. Strikingly, no inhibition of the ABC transporters ABCB1, ABCC1, and ABCG2 could be detected, and molecular docking analyses demonstrated interaction with the MCT1 drug binding pocket in a non-covalent manner.